Numerous polymer-based medical devices have been developed for the delivery of therapeutic agents to the body. In accordance with some typical delivery strategies, a therapeutic agent is provided within a polymeric carrier layer and/or beneath a polymeric barrier layer that is associated with a medical device. Once the medical device is placed at the desired location within a patient, the therapeutic agent is released from the medical device at a rate that is dependent upon the nature of the polymeric carrier and/or barrier layer.
Materials which are suitable for use in making implantable or insertable medical devices typically exhibit one or more of the qualities of exceptional biocompatibility, extrudability, elasticity, moldability, good fiber forming properties, tensile strength, durability, and the like. Moreover, the physical and chemical characteristics of the device materials can play an important role in determining the final release rate of the therapeutic agent.
Phenoxy resins comprise a family of polymers that possess many properties that make them good candidates for use in drug delivery applications. These linear thermoplastic resins of high molecular weight are tough, ductile, amorphous polymers having excellent thermal stability and radiation resistance, adhesive and cohesive strength, and excellent vapor barrier properties. The backbone ether linkages and pendant hydroxyl groups promote wetting and bonding with substrate surfaces. These backbone hydroxyl groups also react with crosslinking groups like isocyanates, phenolic and melamine resins. Further, modification by esterification of the backbone hydroxyl groups which introduces pendant primary hydroxyl groups has been found to produce high molecular weight resins of vastly improved elasticity and permeability.
Materials incorporated into a finished medical device typically undergo a sterilization process. Radiation sterilization, whether by gamma rays, X-rays, accelerated electrons, or other means, is a widely-used method for sterilizing medical devices. Products to be sterilized are typically exposed to gamma rays from a Co-60 or a Cs-137 source or to machine accelerated electrons until the desired dose is received. No toxic agents are involved, and products may be released for sale on the basis of documentation that the desired dose is delivered. For the sterilization of polymeric medical devices, a typical radiation dose of about 1.0-5.0 Mrad (10-50 kGy) or higher, is employed.
Radiation sterilization, however, may modify many important physical and chemical properties of polymeric materials such as the molecular weight, chain length, entanglement, polydispersity, branching, pendant functionality, and chain termination. These changes in the properties may impair the performance of a polymer for a specific use. For example, from a product use standpoint, mechanical properties are important characteristics that may be adversely affected by irradiation of polymers. These properties include tensile strength, elastic modulus, impact strength, shear strength, and elongation. As another example, the drug-eluting properties of a drug eluting stent may be adversely impacted.
For polymers with carbon-carbon backbones, it has been observed that cross-linking generally will occur if the carbons have one or more hydrogen atoms attached, whereas chain-scission generally occurs at tetra-substituted carbons. Polymers containing aromatic molecules, such as phenoxy resins, are generally more resistant to radiation degradation than are aliphatic polymers; this is true whether or not the aromatic group is directly in the chain backbone or not. Thus, both polystyrenes, with a pendant aromatic group, and polyimides and phenoxy resins, with an aromatic group directly in the polymer backbone, are relatively resistant to high doses (>4000 kGy). A summary of the effects of radiation on polymer properties, such as loss of elongation, for a number of common thermoplastics and thermosets is provided in “Polymer Materials Selection for Radiation-Sterilized Products” by Karl J. Hemmerich, Medical Device & Diagnostic Industry Magazine, February 2000, pp. 78-89, the entire contents of which are hereby incorporated by reference.
However, many drug delivery polymers, for example, homopolymers and copolymers containing polyisobutylene, such as a polystyrene-polyisobutylene-polystyrene triblock copolymers, are generally more susceptible to radiation effects and may undergo chain scission during irradiation, especially at the radiation levels typically used for medical device sterilization (e.g., about 2.5 Mrad). Radiation issues are particularly pronounced in medical devices having thin polymer coatings such as the thin coating on the surface of an expandable medical device such as a stent or balloon. Radiation can lead to an unacceptable increase in the surface tack of the coating, which can in turn cause defects in the polymer when it is expanded (e.g., in situations where it is in the form of a coating on the surface of an expandable stent or balloon).
Hence, it would be advantageous to provide polymers that have a variety of desirable properties (e.g., drug release characteristics and biostability/biocompatibility) but which also exhibit improved immunity to radiation-based changes in polymer properties.